Design, synthesis and biological evaluation of new 2,5-diaryl-1,3,4-oxadiazole derivatives as selective cyclooxygenase-2 inhibitors Novel 2,5-diaryl-1,3,4-oxadiazole derivatives as selective cyclooxygenase-2 inhibitors
International Pharmacy Acta,
Vol. 4 No. 1 (2021),
Non- steroidal anti - inflammatory drugs (NSAIDs) are common prescribed medications worldwide for the treatment of inflammatory conditions and pain. However, adverse effects of NSAIDs in long term use have led to investigation of selective cyclooxygenase - 2 (COX-2) inhibitors with reduced adverse reactions, including
gastrointestinal and cardiovascular side effects and nephrotoxicity.
Methods and Results:
In this study, a series of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel selective inhibitors of COX-2 were rationally designed, synthesized, and biologically evaluated. The structures of compounds were confirmed with LC-Mass, IR, and 1H NMR spectra. Based on our results, most of the compounds had proper inhibitory activity against COX-2 similar to celecoxib, and exhibited selectivity towards COX-2 than COX-1. In this series, compound 5f, with nitro group in the R position, revealed the highest inhibitory activity and selectivity (IC50 = 19.6 µM, SI = 108.88) against COX-2. The docking study of compound 5a showed that this structure had appropriate affinity to the active site of the enzyme forming multiple hydrogen bonds.
In summary, these structures will be a valuable lead scaffold to develop new potent and selective COX-2 inhibitors.
- Biological evaluation
- COX-2 inhibitors
How to Cite
2. Onder G, Pellicciotti F, Gambassi G, Bernabei R. NSAID-related psychiatric adverse events: who is at risk? Drugs. 2004;64: 2619-2627
3. Wongrakpanich S, Wongrakpanich A, Melhado K, Rangaswami J. A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly. Aging Dis. 2018;9(1): 143–150.
4. Rouzer C A, Marnett L J. Cyclooxygenases: structural and functional insights. J Lipid Res. 50 Suppl(Suppl). 2009:S29–S34.
5. Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal anti-inflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci. 2013;16: 821-847.
6. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31:986–1000.
7. Sağlık B N, Osmaniye D, Levent S, Çevik U A, Çavuşoğlu B K, Özkay Y, Kaplancıklı Z A. Design, synthesis and biological assessment of new selective COX-2 inhibitors including methyl sulfonyl moiety. Eur J Med Chem. 2021;209:112918.
8. Farzaneh S, Zeinalzadeh E, Daraei B, Shahhosseini S, Zarghi A. New Ferrocene Compounds as Selective Cyclooxygenase (COX-2) Inhibitors: Design, Synthesis, Cytotoxicity and Enzyme-inhibitory Activity. Anticancer Agents Med Chem. 2018;18(2):295-301.
9. Famaey JP. In vitro and in vivo pharmacological evidence of selective cyclooxygenase-2 inhibition by nimesulide: an overview. Inflamm Res. 1997;46(11):437-446.
10. Chen QH, Rao PN, Knaus EE. Design, synthesis, and biological evaluation of linear 1-(4-, 3- or 2-methylsulfonylphenyl)-2-phenylacetylenes: a novel class of cyclooxygenase-2 inhibitors. Bioorg Med Chem. 2005;13(23):6425-34.
11. Rao P, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci. 2008;11(2):81s-110s.
12. Zarghi A, Arfaei S. Selective COX-2 inhibitors: a review of their structure-activity relationships. Iran J Pharm Res. 2011;10(4):655-683.
13. Hoellen F, Kelling K, Dittmer C, Diedrich K, Friedrich M, Thill M. Impact of cyclooxygenase-2 in breast cancer. Anticancer Res. 2011;31:4359–4367.
14. Grösch S, Tegeder I, Niederberger E, Bräutigam L, Geisslinger G. COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J. 2001;15(14):2742-4.
15. Sandler AB, Dubinett SM. COX-2 inhibition and lung cancer. Semin Oncol. 2004;31(2 Suppl 7):45-52.
16. Navarro L, Rosell G, Sánchez S, Boixareu N, Pors K, Pouplana R, Campanera J M, Pujol M D. Synthesis and biological properties of aryl methyl sulfones. Bioorg Med Chem. 2018;26:14, 4113-4126.
17. Zarghi A, Kakhgi S, Hadipoor A, Daraee B, Dadrass OG, Hedayati M. Design and synthesis of 1,3-diarylurea derivatives as selective cyclooxygenase (COX-2) inhibitors. Bioorg Med Chem Lett. 2008;18(4):1336-1339.
18. Rezaee Zavareh E, Hedayati M, Hoghooghi Rad L, Kiani A, Shahhosseini So, Faizi M, Tabatabai SA. Design, Synthesis and Biological Evaluation of Some Oxadiazole Derivatives as Novel Amide-Based Inhibitors of Soluble Epoxide Hydrolase. Lett Drug Des Discov. 2014;11: 721.
19. Kiani A, Rezaee E, Tabatabai SA. Novel Group of Imidazole Derivatives as Atypical Selective Cyclooxygenase-2 Inhibitors: Design, Synthesis and Biological Evaluation. Iran J Pharm Res. 2018;17(Suppl2):78-86.
- Abstract Viewed: 251 times
- PDF Downloaded: 136 times